NPM1 Mutations Do Not Retain a Favorable Prognostic Impact in Adults with Advanced Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Abstract

Introduction: Mutated Nucleophosmin 1 (NPM1 mut) is the most common genetic alteration in AML, seen in 30-35% of newly diagnosed cases. NPM1 mut is associated with a favorable prognosis in newly diagnosed AML. However, the prognostic impact of NPM1 mut in R/R AML has not been defined. We conducted an analysis to characterize the impact of NPM1mut on outcomes of patients (pts) with R/R AML and the impact of specific therapies in R/R NPM1 mut AML.Methods: We identified 1722 pts with R/R AML treated at our institution between Sept 2012 and Dec 2020 and classified them based on their NPM1 mutational status. Pts were treated with either intensive chemotherapy (IC) including combinations of cytarabine (>2gm/m 2/d) and idarubicin with or without a nucleoside analog, or low intensity chemotherapy (LIC) which included either hypomethylating agents or low-dose cytarabine, with or without the addition of venetoclax or targeted therapies. Responses were defined according to the ELN 2017 criteria. Mutational analysis was performed using validated institutional next-generation sequencing panels including panels of genes frequently involved in AML.Results: Among 1722 pts with R/R AML, 204 (12%) had NPM1mut (Table1), with 58% being women (P< 0.0001). In R/R AML, compared to pts with NPM1 wt , those with NPM1 mut had higher white blood cell count on presentation (P< 0.0001) and were less likely to have secondary or therapy-related AML (P< 0.05). Akin to the newly diagnosed setting, pts with NPM1 mut R/R AML frequently harbored a diploid karyotype (61%, P< 0.0001) and FLT3-ITD mutations (49%, P< 0.0001) of which 40% had an allele ratio >0.5.As expected, the probability of achieving a response decreased with each sequential line of salvage therapy in patients with R/R NPM1 mut AML. Following the 1 st, 2 nd, or ≥3 rd line of salvage therapy, rates of complete remission (CR) or CR with incomplete count recovery (CRi) (CR/CRi) were 64%, 54% and 39%, (P>0.05), respectively. However, overall pts with R/R NPM1 mut AML had higher CR/CRi rates compared to those with NPM1 wt within each line of salvage therapy (CR/CRi rate: 1 st salvage: 64% vs 44%, P=0.0001; ≥2 nd salvage: 39%% vs 26%, P=0.02). In the entire cohort, R/R NPM1 mut pts treated with LIC with venetoclax, IC without venetoclax, and LIC without venetoclax demonstrated a CR/CRi of 85%, 75%, and 54% (vs CR/CRi rates 40%, 32% and 50%in NPM1 wt pts for the respective therapies, all P<0.05). This difference in CR/CRi rates between NPM1 mut and NPM1 wt was also noted when analyzing salvage 1 and salvage ≥2 patients separately(Table 2).Despite higher response rates associated with R/R NPM1 mutAML in each salvage setting, there was no difference in in the entire cohort for relapse-free survival (RFS: 5.4 vs 5.4m, 1-year RFS rate: 33% vs 28%, P=0.36) and overall survival (OS: 6.1 vs 5.5m, 1-yr OS rate: 29% vs 24%,P=0.06) between NPM1mut and NPM1 wt. Among pts receiving 1 st salvage treatment, those with R/R NPM1mut had a significantly improved OS compared with NPM1 wt (7.9m vs 5.9m; 1-yr OS 36% vs 28%, P=0.04) (Fig 1A) In contrast ,there was no difference in OS in pts with R/R NPM1mut and NPM1 wt AML receiving 2 nd salvage (6.9m vs 5.3m, 1-yr OS 19% vs 19%, P=0.71) or ≥3 rdsalvage (4.0m vs 4.3m; 1-yr OS 20% vs 17%, P=0.84 ) (Figure 1B and 1C) . The median RFS did not differ between pts with R/R NPM1mut and NPM1 wt AML in 1 st salvage (7.5m vs 5.5m, 1-year RFS rate: 39% vs 31%, P=0.10), 2 nd salvage (2.1m vs 4.6m, 1-year RFS rate: 7% vs 19%, P=0.06), or ≥3 rd salvage (5.7m vs 5.3m, 1-year RFS rate: 25% vs 18%, P=0.85). Among pts with R/R NPM1 mut , there was no difference in CR/CRi rates (53% vs 59%, P=0.55) or OS (5.8m vs 7.7m; 1-yr OS 24% vs 37%, P=0.07) between those with FLT3mut and FLT3 wt.Conclusion: Despite having higher response rates in the R/R setting, patients with NPM1 muthad similar survival outcomes compared with those with NPM1 wtAML, especially in salvage 2 and beyond. Therefore, unlike its impact in ND AML, NPM1mutational status does not confer a favorable prognostic impact in pts with advanced R/R AML. This establishes contemporary baseline CR/CRi and OS expectations for NPM1 mutR/R AML in various salvage settings. Updated co-mutation data and impact of specific therapies on survival and co-mutational groups will be presented at the meeting. [Display omitted] DisclosuresIssa: Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Konopleva: Agios: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; KisoJi: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Rafael Pharmaceuticals: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Cellectis: Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding. DiNardo: ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Foghorn: Honoraria, Research Funding. Borthakur: Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Pemmaraju: Daiichi Sankyo, Inc.: Other, Research Funding; Aptitude Health: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Clearview Healthcare Partners: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Springer Science + Business Media: Other; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Incyte: Consultancy; Samus: Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Celgene Corporation: Consultancy; Blueprint Medicines: Consultancy; MustangBio: Consultancy, Other; Affymetrix: Consultancy, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Short: Jazz Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Astellas: Research Funding; Novartis: Honoraria; NGMBio: Consultancy; Amgen: Consultancy, Honoraria. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Takahashi: Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Andreeff: Amgen: Research Funding; Aptose: Consultancy; Oxford Biomedica UK: Research Funding; AstraZeneca: Research Funding; Breast Cancer Research Foundation: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Glycomimetics: Consultancy; Senti-Bio: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy; Medicxi: Consultancy; ONO Pharmaceuticals: Research Funding. Ravandi: AbbVie: Honoraria, Research Funding; Prelude: Research Funding; Xencor: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Aptitude Health: Honoraria; Jazz: Research Funding; Ascentage: Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Daver: Hanmi: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding.